Airway epithelial cells play a major role in asthma. We recently discovered striking abnormalities in epithelial expression of micro-RNAs (miRNAs) in most subjects with asthma. The overall goal of this project is to understand the nature, causes and consequences of altered epithelial miRNA expression in asthma. Our preliminary studies suggest that IL-13 is responsible for miRNA abnormalities seen in many asthmatics. IL- 17 also alters epithelial miRNA expression, a finding that may be especially relevant for individuals with severe asthma. Epithelial miRNA abnormalities were only modestly reversed by corticosteroid treatment, suggesting that miRNAs may represent novel therapeutic targets for steroid-resistant asthma. Some ofthe miRNAs that are changed in asthma are known to regulate mucociliary differentiation in related systems, but the functional consequences of altered epithelial miRNA expression in asthma remain to be determined. This project has 3 specific aims: 1) Identify epithelial miRNAs that are altered in severe asthma and relate their expression to IL-13 and IL-17 production and mucous metaplasia in the airway, 2) Determine how IL-13 and IL-17 affect miRNA levels in human bronchial epithelial (HBE) cells, and 3) Determine how selected IL-13- and IL-17-regulated miRNAs affect HBE cell gene expression, differentiation and function. These studies will impact asthma research by identifying novel pathophysiologic mechanisms, providing new tools for molecular phenotyping of asthma subsets, and discovering novel therapeutic targets.